The diabetic patients tend to suffer from some disorders such as inhibition of glucose uptake, inhibited glycolysis and increasing beta-oxidation of fatty acid in their peripheral tissues, which cause the use of fat for their body's energy source instead of glucose and lead to some diseases such as hyperglycemia, hyperlipidemia and hyperketonemia.
The beta-oxidation of fat in diabetic patients occurs in a mitochondrial substrate. Carnitine palmitoyl transferase I (CPT I) is an enzyme to transport a higher fatty acid from cytoplasm to a mitochondrial lo substrate, and plays an vital role in limiting the beta-oxidation rate.
Therefore, CPT I inhibitors will be utilized as an effective antidiabetic agent in that they may inhibit the beta-oxidation of higher fatty acids, increase the availability of glucose and exert the hypoglycemic, hypolipidemic and hypoketonemic effects.
The typical compounds belonging to the above mentioned CPT I inhibitors include palmoxirate, clomoxir(POCA) and etomoxir, and these compounds are characterized in that all of them have oxirane carboxylic acid in their most active site.
The inhibitory action of these oxirane carboxylic acid derivatives against the CPT I has yet to be elucidated up to now but it has been assumed that since these derivatives have the stable covalent bonding in the active sites of CPT I within cytoplasm, their inhibition action against the CPT I may contributed to the treatment of diabetes. Therefore, a possible mode of action is that when some nucleophilic substance at the active site of CPT I initiates to attack the epoxide ring structure of oxirane carboxylic acid derivatives, the opened epoxide ring forms a new hydroxyl group and at the same time, CPT I and oxirane carboxylic acid derivative is covalently bonded, thus inhibiting the CPT I activity.
However, the phase II clinical trials of etomoxir had been discontinued owing to some side effects associated with prolonged administration, such as enlarged heart and toxicity in the liver, but its cause has not been explicitly known up to now.